Dose approach matter? A meta-analysis of outcomes following transfemoral versus transapical transcatheter aortic valve replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has gained increasing acceptance for patients with aortic disease. Both transfemoral (TF-TAVR) and transapical (TA-TAVR) approach were widely adopted while their performances are limited to a few studies with controversial results. This meta-analysis aimed to compare the mortality and morbidity of complications between TF- versus TA-TAVR based on the latest data. METHODS: Electronic databases were searched until April 2021. RCTs and observational studies comparing the outcomes between TF-TAVR versus TA-TAVR patients were included. Heterogeneity assumption was assessed by an I2 test. The pooled odds ratios(OR) or mean differences with corresponding 95% confidence intervals (CI) were used to evaluate the difference for each end point using a fixed-effect model or random-effect model based on I2 test. RESULTS: The meta-analysis included 1 RCT and 20 observational studies, enrolling 19,520 patients (TF-TAVR, n = 11,986 and TA-TAVR, n = 7,534). Compared with TA-TAVR, TF-TAVR patients showed significantly lower rate of postoperative in-hospital death (OR = 0.67, 95% CI 0.59-0.77, P < 0.001) and 1-year death (OR = 0.53, 95% CI 0.41-0.69, P < 0.001). Incidence of major bleeding and acute kidney injury were lower and length of hospital stay was shorter, whereas those of permanent pacemaker and major vascular complication were higher in TF-TAVR patients. There were no significant differences between TF-TAVR versus TA-TAVR for stroke and mid-term mortality. CONCLUSIONS: There were fewer early deaths in patients with transfemoral approach, whereas the number of mid-term deaths and stroke was not significantly different between two approaches. TF-TAVR was associated with lower risk of bleeding, acute kidney injury as well as shorter in-hospital stay, but higher incidence of vascular complication and permanent pacemaker implantation.

Predictors of Prosthetic Valve Endocarditis following Transcatheter Aortic Valve Replacement: A Meta-Analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has gained increasing acceptance for patients with aortic disease. A rare but fatal complication prosthetic valve endocarditis (PVE) could greatly influence the clinical outcomes of TAVR. This meta-analysis aims to pin down the predictors of PVE in TAVR patients. METHODS: We performed a systematic search for studies that reported the incidence and risk factors of PVE after TAVR. Data on studies, patients, baseline characteristics, and procedural characteristics were abstracted. Crude risk ratios (RRs) and 95% confidence intervals for each predictor were calculated by the use of random-effects models. Heterogeneity assumption was assessed by an I2 test. RESULTS: We obtained data from 8 studies that included 68,805 TAVR patients, of whom 1,256 (1.83%) were diagnosed with PVE after TAVR. 280 patients died within the 30-days of PVE diagnosis and the pooled in-hospital mortality was 22.3%. The summary estimates indicated an increased risk of PVE after TAVR for males (RR 1.53, P = .0001); for patients with orotracheal intubation (RR 1.65, P = .01), new pacemaker implantation (RR 1.46, P = .003), and residual aortic regurgitation (≥2 grade) (RR 1.62, P = .05); while older age (RR 0.97, P = .0007) and implantation of a self-expandable valve (RR 0.74, P = .02) were associated with a lower risk of PVE after TAVR. CONCLUSION: Clinical characteristics and peri- procedure factors including age, male sex, valve type, orotracheal intubation, pacemaker implantation, and residual regurgitation were proven to be associated with the occurrence of PVE-TAVR. Clinicians should pay particular attention to PVE when treating TAVR patients with these predictors.

Role of TGF-ß1 Signaling in Heart Valve Calcification Induced by Abnormal Mechanical Stimulation in a Tissue Engineering Model.

A tissue engineering model of heart valve calcification induced in a bioreactor was established to evaluate the calcification induced by abnormal mechanical stimulation and explore the underlying molecular mechanisms. Polyethylene glycol (PEG)-modified decellularized porcine aortic leaflets seeded with human valve interstitial cells (huVICs) were mounted on a Ti-Ni alloy frame to fabricate two-leaflet and threeleaflet tissue engineered valves. The two-leaflet model valves were exposed to abnormal pulsatile flow stimulation with null (group A), low (1000 mL/min, group B), medium (2000 mL/min, group C), and high velocity (3000 mL/min, group D) for 14 days. Morphology and calcification were assessed by von Kossa staining, alkaline phosphatase (ALP) content, and Runx2 immunostaining. Leaflet calcification and mRNA and protein expression of transforming growth factor (TGF)-ß1, bone morphogenetic protein 2 (BMP2), Smad1, and MSX2 were measured at different time points. ALP content was examined in two-leaflet valves seeded with BMP2 shRNA plasmid-infected huVICs and exposed to the same stimulation conditions. The results showed that during 14 days of flow stimulation, huVICs on the leaflet surface proliferated to generate normal monolayer coverage in groups A, B, and C. Under mechanical stimulation, huVICs showed a parallel growth pattern in the direction of the fluid flow, but huVICs exhibited disordered growth in the high-velocity flow environment. von Kossa staining, ALP measurement, and immunohistochemical staining for Runx2 confirmed the lack of obvious calcification in group A and significant calcification in group D. Expression levels of TGF-ß1, BMP2, and MSX2 mRNA and protein were increased under fluid stimulation. ALP production by BMP2 shRNA plasmid-infected huVICs on model leaflets was significantly reduced. In conclusion, abnormal mechanical stimulation in a bioreactor induced calcification in the tissue engineering valve model. The extent of calcification correlated positively with the flow velocity, as did the mRNA and protein levels of TGF-ß1, BMP2, and MSX2. These findings indicate that TGF-ß1/BMP2 signaling is involved in valve calcification induced by abnormal mechanical stimulation.

Myeloid deficiency of CCN3 exacerbates liver injury in a mouse model of nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat accumulates in the liver of patients without a prior history of alcohol abuse. The most severe form, nonalcoholic steatohepatitis (NASH), often leads to hepatic fibrosis and cirrhosis with ensuing complications. To date, there is no pharmacologic treatment for NASH. The biological effects of CCN3, specifically its role in the regulation of inflammation, reactive oxygen species production and angiogenesis, have been recently established. Additional data suggests that CCN3 is associated with the development of tumors in the liver yet may be protective of liver fibrogenesis. Currently, the role of CCN3 in NAFLD/NASH remains unexplored. Therefore, the objective of our investigation was to decipher the role of myeloid-deficient CCN3 in the pathogenesis of NASH and the underlying mechanisms of CCN3 in modulation of hepatic function. Wild type and myeloid CCN3-deficient mice were fed a methionine- and choline-deficient diet to induced NASH. Increased lipid, cholesterol, and cholesterol ester accumulation was observed in myeloid CCN3-deficient mice when compared to the control group. This disease state was associated with alterations of key genes involved in lipid synthesis, ß-oxidation and lipid uptake. Additionally, the levels of important molecules critical for inflammation, ROS generation, ER stress and liver injury were significantly elevated; as was the observed severity of hepatic apoptosis and necroptosis. Therefore, CCN3 is critical for protection from hepatic apoptosis and necroptosis in our induced NASH model and our findings suggest that CCN3 can be exploited as a therapeutic target for the treatment of NASH.

CCN3 Regulates Macrophage Foam Cell Formation and Atherosclerosis.

Recent studies implicate the Cyr61, CTGF, Nov (CCN) matricellular signaling protein family as emerging players in vascular biology, with NOV (alias CCN3) as an important regulator of vascular homeostasis. Herein, we examined the role of CCN3 in the pathogenesis of atherosclerosis. In response to a 15-week high-fat diet feeding, CCN3-deficient mice on the atherosclerosis-prone Apoe-/- background developed increased aortic lipid-rich plaques compared to control Apoe-/- mice, a result that was observed in the absence of alterations in plasma lipid content. To address the cellular contributor(s) responsible for the atherosclerotic phenotype, we performed bone marrow transplantation experiments. Transplantation of Apoe; Ccn3 double-knockout bone marrow into Apoe-/- mice resulted in an increase of atherosclerotic plaque burden, whereas transplantation of Apoe-/- marrow to Apoe; Ccn3 double-knockout mice caused a reduction of atherosclerosis. These results indicate that CCN3 deficiency, specifically in the bone marrow, plays a major role in the development of atherosclerosis. Mechanistically, cell-based studies in isolated peritoneal macrophages demonstrated that CCN3 deficiency leads to an increase of lipid uptake and foam cell formation, an effect potentially attributed to the increased expression of scavenger receptors CD36 and SRA1, key factors involved in lipoprotein uptake. These results suggest that bone marrow-derived CCN3 is an essential regulator of atherosclerosis and point to a novel role of CCN3 in modulating lipid accumulation within macrophages.